CLIN. RESEARCH PRACTICES
&
DRUG
REG.
AFFAIRS,
6(3),
147-157 (1988)
THE CLINICAL DATA
STORY
By
Robert
J.
Bronstein
Pharmaceutical Industry Consultant
Morris
Plains,
NJ
07950
To assess the value of a drug in the treatment, prevention, or diagnosis
of
a disease is a
complex process that takes an average of eleven years, at a cost of
$90
million. The drug
development process has four phases: Drug Discovery, Pre-Clinical Development, Clinical
Development, and Regulatory Submission.
A
DRUG DISCOVERY PHASE
1
-
5
Years
Of
Every
10,000
Molecules
PRE-CLINICAL
DEVELOPMENT PHASE
1
-
2
Years
20
May Be Further Tested
CLINICAL DEVELOPMENT
PHASE
3
-5
Years
4
May Be Recommended For
CI i n ica
I
Testi ng
FDA APPROVAL
3
Years
1
May Be Accepted
147
Copyryhf
0
1988
by
Marcel Drkker.
Inc
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148
BRONSTEIN
The Clinical Data
Story
looks at the process of developing a drug as
a
therapeutic article of
commerce from the point in time it is launched into clinical investigations until it is
submitted
to
the Food and Drug Administration.
Before walking through ‘The Clinical Data Story”, it is helpful
to
understand many
of
the
processes that take place as they are defined by
the
Bureau of Biologics of the Food and
Drug Administration.
THE
MVESTIGATIONAL
NEW
DRUG APPLICATION
(IND)
Prior
to
entering clinical investigation, an IND must be filed with the Food and Drug
Administration.
The Investigational New Drug application (IND) includes:
Data on in vivo (animal) and in vitro (test tube) studies that show safety and efficacy.
0
Characterization of what
a
molecule looks like.
Manufacturing and Control Procedures.
0
Protocols explaining how
a
drug will be tested.
Qualifications
of
the investigators that will conduct clinical trials.
Once filing of
an
IND
takes place, the FDA has thirty days
to
review the application. If
there are no problems identified, Phase I Clinical Trials
can
begin.
PHASE
I
-
CLINICAL PHARMACOLOGY TRIALS
This is the initial introduction of
a
new therapeutic in man. Normal male volunteers are
studied
to
determine levels of tolerance,
as
well as preliminary dose-ranges for safety.
Between twenty and eighty healthy volunteers, generally male, are subjected
to
drug
therapy.
PHASE
I1
-
CLINICAL TRIALS
Phase
II
studies are designed
to
demonstrate effectiveness and relative safety of a
therapeutic agent in a diseased patient population. One hundred
to
two hundred patients
under tightly controlled protocols are entered into therapy.
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149
THE
CLINICAL
DATA
STORY
Clinical
Operatin Plan
Time andtvent
Schedule
Budget
Operating Investigators
Plans
as
Figure
1
Planning
of
Clinical
Program
PHASE
111
-
CLINICAL TRIALS
Phase
III
clinical trials consist of studies with and without control groups that are planned
to
treat thousands
of
patients. Phase
III
studies are intended
to
gather evidence of
tolerance, effectiveness, safety, and
to
identify a profile of adverse drug reactions.
THE
NEW
DRUG
APPLICATION (NDA)
Once
a
company’s clinical and regulatory bodies are confident that a new therapeutic agent
is safe and effective, and data is available
to
support conclusions, an
NDA
is submitted for
approval
to
market a product.
THE
CLIMCAL
DATA
STORY
I.
THE
CLINICAL PROGRAM
The Clinical Data
Story
follows a presentation combining a schematic
of
the clinical
development cycle with annotations. Each annotation is preceded by a numeral that
references back
to
a specific activity in the schematic.
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150
BRONSTEIN
In identifying the therapeutic benefit and market potential of a new drug, it is necessary
to
receive feedback from three sources: Marketing, Management, and Literature. Once input
from these sources are melded together,
an
organization can set the direction for a clinical
program.
1.1
1.2
1.3
1.4
1.5
Before
a
clinical program can start, a clinical operating plan must be prepared
identifying the activities of development
a
drug will follow. It is also time
to
determine the clinical operating budget and time and events schedule.
Once identified the Clinical Operating Plan (COP), Time and Events Schedule
(TES),
and budget must be presented to management for approval.
After sufficient review, management agreement in the form of budget approval
will hopefully be received.
As
with any budget, as you proceed forward and receive feedback, revisions are
likely to occur.
We are now ready
to
put the Clinical Operating Plan into action. Protocols and
case report forms are designed for studies identified in the Clinical Operating Plar
and requests for bulk materials are initiated
so
that
Pharmacy can begin the
process of preparing drug supplies.
1.6
The Medical Division performs
an
extensive review of study protocols and case
report forms.
1.7
The Medical Division identifies potential study investigators.
1.8
The Information Handling Division (Biomedical Information) reviews the protocol
and case report form and comments on potential concerns.
11. CLINICAL PROGRAM
INITIATION
Once the basic structure of an investigational clinical program
is
determined, clinical
studies which are components of the program may start.
2.1
As
remaining touches are made
to
protocol and case report form it is time to
identify potential investigators and make appropriate contact for study placement.
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THE
CLINICAL
DATA
STORY
‘As
Investigators
are
identified and
committed
to
conduct
a
study,
Steps
2.2
1
to
2.4
are
performed
concurrently.
151
U
U
n
I
Package
and
Ship
Cllnlcal
Visit
and
Pre-
Clinical Grant
Figure
2
Clinical
Program
Initiation
2.2
The pharmacy will receive Packaging and Labeling Requests fron the Medical
Department and review specific details
so
that preparation and distribution
of
medication will follow
on
schedule.
2.3
A Clinical Monitor or Clinical Research Associate will visit selected investigators
and perform
a
pre-study site audit. At the same time there will be
a
review of
specific study interaction documents that must be completed
prior to
study
start.
These documents are defined in
2.6.
2.4
A case report
form
that is elegant, professional, and easy
to
complete is important
to
smooth study flow. Professional off-set printing is normally utilized for this
process.
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152
BRONSTEIN
We
have
now
made
Pid
investigator
selection
and
are
ready
ta
begin
initiating
clinical
studies.
2.5
The pharmacy will prepare individual unit dosing packages
to
supply each patient
entering the study with the correct amount of medication as specified in the study
protocol.
2.6
In
Step
2.3
reference
to
initiation documents that are completed by the study
investigator
was
made. These documents are:
0
Investigational Review Board (ZRB) Approval
0
Patient Informed Consent
0
Signed Investigator’s Statement
Investigator’s
/
Co-investigator’s Curriculum Vitae
0
Budget Estimate
2.7
Under separate package from study medication, case report forms are supplied
to
investigational sites.
2.8
As stated, shipment of clinical supplies is performed separate from case report
form shipment. The reason for this is potential clearance delays with customs of
foreign countries.
2.9
We have finally achieved a major milestone in clinical development; the study
Start.
111.
CONDUCT CLINICAL PROGRAM AND BEGIN DATA PROCESSING
SET-UP
The clinical program
is
initiated with
the
opening of study sites and, with a little luck,
patient enrollment
is
progressing smoothly. In anticipation of receiving case report forms,
data processing activities begin.
3.1
A system
to
expedite the entry
of
case report forms must be implemented, tested
and ready for use when clinical study data is received.
3.2
Having identified in the study protocol study rules and regulations, a database
must be designed that will assist the Clinical Monitor and Clinical Research
Associate in monitoring progress of
a
clinical study.
3.3
In the medical writing group,
a
facsimile
or
“mock-up” clinical report for the study
is produced and reviewed with the Clinical Study Monitor and Study Statistician.
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THE
CLINICAL
DATA
STORY
153
Create
6
Tost
Data Entry
System
Plan
Clinical
Database
3.2
Create
Facsimile
Clinical
Routines
1
3.1
J
n
Fi
ure 3
Conduct c4inical Program
3.4
Routines
for
statistical analysis that were identified in the study protocol are
prepared by the Study Statistician in anticipation of the database becoming
available. Tabular displays and graphic presentations are also prepared for
inclusion in the statistical appendix
of
the clinical study report.
3.5
Let
us
not forget the continued activities of the Clinical Monitor and Clinical
Research Associate who are overseeing the clinical study
as
it progresses toward
completion.
The
study
Is
now
in
full
opetatlon
and
scheduled
actlvitles
are performed
1
in
preparation
of3.8,
the
Monthly
Clinkel
Review
Meeting.
-I_L-
3.6
The Ongoing Monitoring Service
(OMS)
is an operation performed by the Study
Statistician.
OMS
tracks the progress of a study, feeding information of potential
concern back
to
the Clinical Monitor and Clinical Research Associate.
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EnterNerify
Data from
Case Report
Forms
Generate
Edit Reports
//
Code and
Classify
Information
Report Forms
//
Q
BRONSTEIN
-
Yes
Case Report
Form Review
by
Clinical
Monitor
4.1
Official
Locking of
V
Identified?
1
No
c3
Figure
4
Process
Data
from
Clinical
Program
3.7
During periodic visits
to
the study center, case report
forms
are retrieved and
a
Clinical Contact Report is prepared, reporting observations made by the Clinical
Research Associate.
3.8
Monthly Clinical Review Meetings are held with management, reviewing clinical
program
status
from
a global point of view.
IV.
PROCESS
DATA
FROM
CLINICAL
PROGRAM
Clinical case report
forms
are arriving at regular intervals and must be processed and
reviewed in
a
timely manner.
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THE
CLINICAL
DATA
STORY
155
4.1
4.2
4.3
4.4
4.5
4.6
4.7
4.8
4.9
4.10
As clinical case report forms are retrieved from study centers, they are reviewed
by the Clinical Monitor and Clinical Research Associate prior
to
being forwarded
to
the Clinical Data Processing Group.
A copy of the original case report form is supplied to the Clinical Data Coder (CDC)
for review and classification prior
to
computer entry. The Clinical Data Coder
classifies information
on
the case report form for consistency in reporting.
Information such as clinical side effects and concomitant medications are
classified using one of many available classification dictionaries.
The case report form is keyboard entered and verified prior
to
transmission to
storage in the clinical study database. A screen of edits is imposed on the data
prior
to
database inclusion
to
avoid “uncleansed” data being combined with
lnedically cleansed data.”
As data further matures in our process, it is moved into the clinical database for
the study.
The Registration Lock Date (RLD) is another milestone in our process. This is the
last day in which
a
patient may be enrolled for inclusion in the clinical study.
At predetermined intervals, “intelligent” edits are circulated and reviewed by the
Medical Monitor, Statistician, and Medical Writer. Corrections are noted on the
edit report and the process continues.
Iferrors are identified in the edit reports, reprocessing of Steps
4.2,4.3,4.4
and
4.6
will
occur.
Ifno
errors are identified, Step
4.8
will occur.
The Data Lock Date (DLD) is a milestone that identifies the last day a case report
form will be accepted for inclusion in the clinical study database.
Final cleanup of the database is taking place and if no errors are identified, the
process proceeds to
4.10
database lock.
The
database lock is a milestone in which the Study Monitor, Study Statistician
and Medical Writer agree that
no
further changes to the database will be made.
V.
CLINICAL DOCUMENT PREPARATION
5.1
Final databases are now released for use by all study personnel and the following
documents for the New Drug Application are prepared.
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156
BRONSTEIN
Documrnt
Proparation
Prepare
the
Following
Reports
I
\
Clinical
Pharma-
Multicrntrr
Clinical
Multicrntrr
Clinical
Annotatrd
Packagr
inson
Siomrtrics
Rrports
kirntific
Rational
h
Drug Purporr
Ovrrall
Rosults
h
Conclusions
Volumr of
Advcrsr
Rractions
h
Patirnt
L
Dropouts
Summary of
Clinical
Litrraturr
Summary of
Studios
1
Summary
of
Special
Studios
I
Summary
of
DOSO
Ranging
Studios
Summary
of
Controllrd
Clinical
Studios
c
Figure
5
Clinical Document Preparation
VI. REGULATORY SUBMISSION
We are now approaching a series of milestones that are essential
to
a successful NDA
submission
to
the Food and Drug Administration (FDA).
During-Cheprocesses that
follow, meetings are conducted with FDA. These meetings are called pre-NDA
meetings.
6.1
As the various componenta of the NDA are completed, Document Review Meetin
s
are
scheduled. Present at review meetings are representatives from Regulatory, Meiical,
Statistics, and Medical Writing.
6.2
As indicated and agreed
to
by the Clinical Document Review Committee, revisions
are made
to
clinical documents.
6.3
A further review
of
the entire NDA
is
conducted by the Regulatory
Affairs
Department.
6.4
When all reviews are completed, the NDA receives ita final cosmetic touches and is
packaged
for
submission
to
the FDA. As the FDA reviewer poses questions, they
are distributed and answered by the appropriate group in R&D.
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THE
CLINICAL
DATA STORY
157
Document
Review
Meeting
Re ulaqory
Appropriate
to
FDA
0
Approval
Figure
6
Regulatory Submission
6.5
A
banner milestone
-
the
NDA
is
received
at
FDA.
6.6
If
all things
go
as planned, in approximately
23
-
3
years, a company can expect
to
receive an approval letter
from
the
FDA.
3UM
M
A
RY
Am
in any
process,
thcre
are"do's
and dont's."
For
the
New
Drug
Application
(NIIAJ
they
are identified in
the
federal reglstrr.
Every
company
has
Its
own way
of
planning, inltiatlng, conducting,
procensing,
and documenting the results
of
a
clinical
program.
No
one
way
is
right,
and
no
one
way
is
wrong,
The
bottom
llne
for
all
of
us
is
to
Iiring
new therapeutic
agentrr
to
the
marketplace
where they
can
be
prescribtad
Por the health
care
needs
of
saciety,
__
__
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